The long term goal of the Genomics of AML (GAML) Program Project is to discover all the genetic alterations that occur in the genomes of AML cells derived from adult patients, and to validate the importance of these alterations for disease susceptibility, initiation, progression, relapse, and resistance. The short-term goal is to define the most frequently occurring genetic changes that affect clinical outcomes, since these are the ones most likely to have an impact on therapy. We will use a variety of experimental platforms to define these genetic changes, including routine cytogenetics/FISH, array-based comparative genomic hybridization (CGH), RNA profiling, and high-throughput DNA resequencing. All of the exons of approximately 450 selected genes will be resequenced in a "discovery set" of 47 patients with FAB subtypes 0-4, and all changes will be evaluated in the germline to see whether they are acquired. A second discovery project will comprehensively analyze the genes of chromosome 7, since loss of part or all of this chromosome occurs frequently in several malignant myeloid diseases. Using a "validation set" of 94 AML samples with mature clinical data from the CALGB, we will attempt to rapidly define the genetic changes that alter clinical outcomes. The importance of genetic changes will also be verified in the Project Laboratories using biochemical, cellular, and murine model systems. Mouse models of AML will be used not only to identify genes for resequencing in humans, but they will be used to verify the importance of mutations discovered by resequencing human samples. Our group is a unique position to perform these studies because of key components already in place at Washington University Medical School, including the Siteman Cancer Center, the Genome Sequencing Center, the Stem Cell Transplant/Leukemia Program, and an extensive AML mouse-modeling program. We will use information gained from these studies to create molecular diagnostic tools for disease stratification, and we will identify candidate genes for targeted therapeutics. The identification of the mutations that occur in the genomes of AML cells will contribute greatly to our understanding of the pathogenesis of this disease, and we hope that it will ultimately improve our ability to cure these patients.